tbuckley/cabot-search huggingface dataset:
Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study.
Authors: Philippe E. Spiess, Roger Li, Petros Grivas, Andrea Necchi, Dean C. Pavlick, Richard S.P. Huang, Douglas I. Lin, Natalie Danziger, Jeffrey S. Ross, Joseph M Jacob, Gennady Bratslavsky
Journal: Journal of Clinical Oncology (2023)

4 Background: TMB has emerged as a major biomarker of efficacy in immune checkpoint inhibitor (ICPI) therapies in the neoadjuvant, adjuvant and metastatic disease setting in a wide variety of malignancies, but not in PSCC. Methods: 397 clinically advanced (local major recurrence and/or metastatic disease) PSCC underwent hybrid capture-based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Trinucleotide mutation signatures were evaluated (Alexandrov, et al. 2013). Genome-wide loss of heterozygosity (gLOH) was determined using validated pipelines and excluding whole-arm and whole-chromosome events. TMB was categorized into three cohorts: &lt;10 mutations/Megabase [muts/Mb] (low), 10-19 muts/Mb (high), and &gt;20 muts/Mb (very high). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3) and defined as tumor proportion score (TPS) &gt;1. The presence of HPV16/18 was determined by next generation sequencing (NGS). Statistical comparisons were corrected for multiple comparisons using the Bonferonni method. Results: There were 339 (85.4%) TMB low, 40 (10.1%) TMB 10-19 and 18 (4.5%) TMB very high PSCC cases in this study. The mean age of PSCC with very high TMB at 70.1 yrs was older than for TMB low at 63.4 yrs (p=.08). There were no significant differences in genomic ancestry among the 3 groups. The TMB 10-19 and TMB very high tended to feature an APOBEC genomic mutational signature more than the TMB low PSCC cases (74 and 76% vs 44%). MSI high status was absent in the TMB low PSCC, but was present in 7.5% of the TMB 10-19 and 11.8% of the TMB very high cases. gLOH levels above 16% were similar in all 3 groups and ranged from 6.2 to 9.4%. GA associated with differences in TMB status in the PSCC cases included higher PIK3CA GA in TMB 10-19 (40.0%) vs TMB low (18.3%; p=.035) and TMB very high (66.7%) vs TMB low (p=.0002). CDKN2A GA were higher in TMB low (45.7%) than in the combined TMB 10-19 + very high (25.9%; p=.049). GA in KMT2D were higher in the combined TMB 10-19 + very high (29.3%) than the TMB low PSCC (7.7%; p=0002). FGFR3 GA were similar in all 3 groups. PD-L1 expression was not significantly different among the 3 groups with TMB low (78.3%), TMB 10-19 (64.2%) and TMB very high (54.5%). HPV identification was more frequent as TMB increased: 28.3% for the TMB low, 50.0% for the TMB high and 58.8% for the TMB very high groups. Conclusions: The evaluation of PSCC by CGP based on TMB levels revels significant differences in biomarkers for the near 15% of cases that have TMB &gt;10 muts/Mb. Further study of TMB as a biomarker in ICPI-based clinical trials for advanced PSCC appear warranted.
Phase II trial of intermittent therapy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with front-line ipilimumab and nivolumab (Ipi/Nivo).
Authors: Laeth George, Wei Wei, C. Marcela Diaz-Montero, Allison Martin, Neil Vyas, Arnab Basu, Katy Beckermann, Amanda Nizam, Christopher Eing Wee, Timothy D. Gilligan, Shilpa Gupta, Brian I. Rini, Moshe Chaim Ornstein
Journal: Journal of Clinical Oncology (2023)

672 Background: The combination of ipilimumab and nivolumab (Ipi/Nivo) is approved for patients (pts) with treatment-naïve, intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), but duration of therapy and safety/efficacy of re-induction at progression is unknown. A phase II trial of intermittent Ipi/Nivo with re-induction at progression was conducted (NCT03126331). Methods: Patients with treatment-naïve mRCC were treated with induction Ipi/Nivo followed by up to 24 weeks (+/- 8 weeks) of maintenance Nivo. Pts who achieved a complete response (CR) or partial response (PR) were eligible for inclusion and entered a treatment-free observation period. Pts were restaged every 12 weeks. Pts with no disease progression (PD) remained off therapy. Upon PD, pts were re-challenged with 2 doses of Ipi/Nivo every 3 weeks, with 1 or 2 more doses at physician discretion. The study objectives were to estimate success rate of observation in pts who achieve a CR/PR (defined by 50% of CR/PR pts sustaining a treatment-free interval of at least 9 months), and to assess toxicity in pts undergoing re-induction. The study was closed early given poor accrual in the rapidly changing mRCC treatment landscape. Results: Nine pts were included; 89% male, median age 57, 78% prior nephrectomy, 67% clear-cell histology, all had KPS ≥ 80%, and 78% were intermediate-risk by IMDC criteria. All pts had 4 doses of induction Ipi/Nivo. Response to Ipi/Nivo and Nivo maintenance prior to enrollment was 33% CR and 67% PR. Most (78%) pts patients have remained off therapy, with a median treatment-free interval (TFI) of 34.3 months (range, 8.7-41.8). The success rate of 0.78 (95% CI: 0.40-0.97) exceeded the pre-specified threshold of 50%. Two pts had PD off therapy (3 and 8 months after therapy cessation; both with best initial response of PR). Both received 2 cycles of re-induction Ipi/Nivo. No grade 3 or greater toxicities occurred with re-induction, but both pts developed PD at their first scans after re-induction. Conclusions: This pilot prospective study demonstrates that patients with a radiographic response to Ipi/Nivo can have prolonged treatment-free intervals. Further studies of de-escalation strategies are warranted. Correlative investigations for this trial are ongoing. Clinical trial information: NCT03126331 .
Physician preferences for nonmetastatic castration-resistant prostate cancer treatments: A discrete choice experiment among men in mainland China.
Authors: Yu Fan, Shiyun Huang, Rui Xu, Zhisong He
Journal: Journal of Clinical Oncology (2023)

88 Background: A range of medication options are available for non-metastatic castration-resistant prostate cancer (nmCRPC), with varying efficacy and safety profiles. We used a discrete choice experiment (DCE) to explore how physicians make treatment decisions between adverse events (AEs) and survival gains in nmCRPC in mainland China. Methods: Physicians’ preferences for medication attributes were assessed through an online survey including 14 treatment choice questions, each comparing 2 hypothetical treatment profiles, which varied safety (fatigue, skin rash, cognitive problems, falls, and fractures) in terms of severity and frequency and efficacy (overall survival [OS] and time to pain progression [TPP]) in terms of duration of effect. Preference weights and importance scores for each attribute were estimated using random parameters logit models. The amount of survival gain physicians were willing to trade off for a reduction in specific AEs was also estimated. Results: In total, 80 physicians who had experience in treating nmCRPC patients were involved in this study. Physicians’ duration of clinical practice was about 18.4±7.39 years. In addition, 57.6% of participants were from regions with more developed economics, including North, East and South China. The results indicated that physician preferences were logically ordered, with higher efficacy and lower risks for AEs being favored over lower efficacy and higher risks for AEs. The most important attributes for treatment decision were OS (Relative importance, RI = 29.2%), serious fracture (RI = 24.4%), serious fall (RI =15.4%) and TPP (RI =10.6%). Comparing non-serious AEs including fatigue, skin rash and cognitive problems, physicians emphasized the risk reduction of fatigue the most. The trade-off analysis between OS and adverse events suggested that physicians were willing to trade 7.5 and 4.7 months of OS to reduce the risk of severe fracture from 8% to none, and the risk of serious fall from 8% to none. In an exploratory subgroup analysis, it was found that physicians with more than 15 years of clinical practice put more emphasis on overall survival, risk of serious fracture, and risk of serious fall compared to less experienced physicians (≤15 years). Physicians from regions with more developed economics tended to put more value on reduction of AEs as compared to physicians from the rest regions. Conclusions: OS is the most important attribute for physicians when treating nmCRPC patients. Physicians were willing to trade the duration of OS to reduce the risk of serious adverse events. These results emphasize the importance of carefully balancing therapies’ benefits and risks to ultimately optimize the overall quality of nmCRPC patients’ survival.
A phase II study to evaluate the safety, pharmacodynamics and efficacy of entinostat in combination with nivolumab plus ipilimumab in patients with renal cell carcinoma previously treated with nivolumab plus ipilimumab or nivolumab alone.
Authors: Roberto Pili, Nabil Adra, Theodore F. Logan, Heather Burney, Michael B. Atkins
Journal: Journal of Clinical Oncology (2023)

668 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that histone deacetylase (HDAC) inhibitors have antitumor effects in combination with PD-1 inhibition by inhibiting the function of Tregs and MDSCs in preclinical models. We hypothesized that HDAC inhibition may resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we opened a Phase II clinical study with the HDAC inhibitor entinostat and the immune check point inhibitors nivolumab (nivo) and ipilimumab (ipi) in clear cell RCC pts previously treated with nivo + ipi or nivo alone. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a dose de-escalation, two stage, phase II clinical trial with a safety lead-in. Due to a funder decision, enrollment was halted after completion of accrual to the safety lead in group. Pts received oral entinostat at a dose of 5 mg (dose level 1) or 3 mg (dose level 2) every 7 days, continuously, with nivo at a dose of 3 mg/kg mg IV every three weeks in combination with ipi at a dose of 1 mg/kg every 3 weeks X 4 doses. Then, nivo 480 mg was continued every 4 weeks. Results: A total of 12 pts with prior nivo+ipi or nivo treatments was enrolled. Dose level 1 (5 pts enrolled) was completed with the following DLTs: thrombocytopenia, nausea and vomiting, pneumonitis. Seven pts were enrolled on dose level 2 which was established as the recommended phase II dose. The most common treatment-related toxicities were fatigue, hypophosphatemia, neutropenia and thrombocytopenia. All were transient. Most of the pts had 2 or more prior treatments. Four pts achieved a partial response, with 3 out 4 pts previously treated with nivo alone (ORR 33%; 95% CI 9.9-65.1). The median PFS was 11.1 months (CI 1.3-26.4). We collected blood samples to conduct several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and nivo+ ipi is relatively well tolerated and may be active in pts with RCC. Clinical trial information: NCT03552380 .
Overall survival (OS) and efficacy results of second-line treatment in patients (pts) with metastatic clear cell renal cell carcinoma (mRCC) treated in the randomized phase II BIONIKK trial.
Authors: Yann-Alexandre Vano, Letuan Phan, Audrey Simonaggio, Mostefa Bennamoun, Diane Pannier, Christine Chevreau, Delphine Borchiellini, Denis Maillet, Marine Gross-Goupil, Brigitte Laguerre, Christophe Tournigand, Philippe Barthelemy, Elodie Coquan, Gwenaelle Gravis, Cheng-Ming Sun, Maxime Meylan, Wolf-Hervé Fridman, Catherine Sautès-Fridman, Réza Elaidi, Stephane Oudard
Journal: Journal of Clinical Oncology (2023)

607 Background: To date, no biomarker of efficacy of nivolumab+/-ipilimumab (N+/-I) or anti-VEGFR TKI has been prospectively validated in mRCC. The BIONIKK trial showed promising objective response rate (ORR) and progression-free survival (PFS) with these treatments in first line (L1) after selection by tumour molecular group. We report OS and efficacy results of the second-line (L2) treatment. Methods: BIONIKK is a French multicentre non-comparative phase II trial, randomising 199 mRCC pts to receive N (58), NI (101) or TKI (40) in L1 according to four molecular groups (ccrcc1-4). ORR and PFS were already reported. With an additional follow-up of ≥20 months, we report OS from randomization and from the start of L2, as well as ORR and PFS with a TKI in L2 by molecular group. Results: With a median follow-up of 42.1 months (40.5-45.2), 86 (43%) patients died: 27/58 (46.5%), 39/101 (39%) and 20/40 (50%) in the N, NI, and TKI arm, respectively. Median OS were 43.4 months (95%CI=31.4-NR) with N, 52.7 months (95%CI=46-NR) with NI and 38.1 months (95%CI=33.2-NR) with TKI (table). 175 (88%) patients discontinued first-line treatment, including 20 deaths, and 129 (74%) received a L2, 38/58 (65.5%), 64/101 (63%), and 27/40 (67.5%) after N, NI and TKI, respectively. The most frequent L2 received after N+/-I was a TKI in 96/102 (94%) pts, including cabozantinib in 49, sunitinib/pazopanib in 32, axitinib in 13, and lenvatinib in 2. N was the most frequent L2 after TKI, 20/27 (74%). ORR with TKI in L2 was 28.5% (10/35) after N, 39% (24/61) after NI and 80% (4/5) after TKI, with marked benefit in ccrcc2 pts (table). The mPFS with TKI in L2 was 8.2 (95%CI=6.9-19.3) after N, 11.4 (95%CI= 8.9-16.8) after NI, and 12.1 (95%CI =11.4-NR) months after TKI, with a higher benefit in ccrcc2 pts (vs. ccrcc1+4, p=0.04). Conversely, ORR and mPFS with N after TKI in ccrcc2-pts were 12.5% (2/16) and 5.4 (2.6-NR) months, respectively. Median OS L2 was reported in the table. The updated ORR and PFS in L1 will presented at the Meeting, as well as PFS2 and efficacy by TKI type in L2. Conclusions: We report for the first-time OS and L2 efficacy results by molecular group in a randomized trial. Molecular selection also has an impact on treatment efficacy in L2. These results, together with those reported in L1, can inform clinicians on the best treatment sequence in L1-2. Clinical trial information: NCT02960906 . [Table: see text]
Clinical features and prognosis of patients who undergo renal transplant with urothelial carcinoma.
Authors: Juan Li, Xieqiao Yan, Bixia Tang, Siming Li, Li Zhou, Huayan Xu, Jun Guo, Xinan Sheng
Journal: Journal of Clinical Oncology (2023)

527 Background: Malignant tumor has been identified as one of the three major causes of death for kidney transplant recipients. This study collected the clinical data of UC patients after kidney transplantation in our center retrospectively, and explored the natural course of disease and response to systemic treatment of this special subgroup of patients. Methods: 1332 consecutive uc patients diagnosed pathologically in our department from 2012 to 2022 were collected, including 26 renal transplant pts. Data were collected, including gender, age, pathological grade, primary site, initial diagnosis stage, metastasis time, site, systemic treatment plan and response to treatment. Kaplan-Meier survival analysis was used to explore the survival and prognostic factors of uc patients after renal transplantation. Results: 1332 consecutive uc patients from Sep 2012 to Sep 2022 in our department were collected, including 26 pts (1.95%) after renal transplantation. 7 males (26.9%).，overall median age of diagnosis 59.0y (40-79y), 24 pathological high-grade (92.3%), 6 cases are with other differentiation (23%), 7 cases (63.65%) her2 IHC 2~3+ in 11 tested cases. Primary site includes 8 renal pelvis (30.8%), 7 ureter (26.9%), 3 bladder (11.5%) and 8 multiple (30.8%). T1, T2, T3, T4 and Tx accounted for 1 (3.8%), 8 (30.8%), 14 (53.8%), 0 and 3 (11.6%)，with lymph node metastasis in 2 (7.7%). Initial stage I, II, III and IV were 3.8%, 69.2%, 11.6% and 15.4% The median survival time of the four groups was 73.4, 38.0, 18.3 and 13.9 months respectively. The median disease-free survival time of 24 patients after radical surgery was 16.0 months (95% CI: 13.2-27.8m), and 11 patients (42.3%) relapsed within one year after surgery. Among systematic treatment, 24, 9 and 3 patients received the first-, second- and third line treatment. First-line includes nab-ptx+gem (7), ptx+gem+endo/bev (6), ptx+gem+cisplatin+endo/bev (4), gem+cisplatin (3), ADC (2 ), gem+carboplatin (1) and gem+oxa (1). Second-line includes nab-ptx based chemo (5), ADC (2), ptx+gem+cisplatin+endo (1) and ptx+sorafenib (1). Third-line includes nab-ptx +gem+cisplatin+bev (1), gem+cisplatin+sotan (1) and everolimus+cisplatin (1). The mPFS of first-, second-, and third-line were 6.5 months (95% CI: 6.4-17.7 m), 2.6 months (95% CI: 1.6-5.3 m) and 2.0 months (95% CI: 1.8-21 m). The mOS was 15.3 months (95% CI: 8.4-15.1 m), 11.6 months (95% CI: 5.0-16.3 m) and 8.0 months (95% CI: 1.6-13.0 m). The most common distant metastasis in late stage included lymph node in 16 cases (61.5%), lung in 12 cases (46.1%), bone in 7 cases (26.9%) and liver in 5 cases (19.2%). Conclusions: Urothelial carcinoma in renal transplant patients has higher degree of malignancy, nearly half of the patients have rapid recurrence and metastasis after operation. It seems these sub-group patients have higher her2 (IHC 2-3+) status.
Biology and usefulness of [-2]proPSA as a prognostic marker in CRPC patients.
Authors: Yoshiyuki Miyazawa, Yusuke Tsuji, Seiji Arai, Yoshitaka Sekine, Kazuhiro Suzuki
Journal: Journal of Clinical Oncology (2023)

242 Background: Prostate health index (phi) using -2proPSA (p2PSA), which is a precursor of PSA, has been reported to be useful as a marker for predicting the presence of cancer in the gray zone with a PSA value of 4-10 ng/ml. There is no detailed report on the biology of p2PSA in castration resistant prostate cancer (CRPC) patients and it is unknown. We retrospectively investigated the biology of p2PSA and its usefulness as a marker using CRPC patient's samples. Methods: The study was performed using samples from a prospective study of CRPC patients treated with enzalutamide. We examined 98 pre-enzalutamide treatment serum samples that can measure p2PSA. The samples were collectively measured by Beckman Coulter (Tokyo, Japan). We also examined the correlation between the measurement results of p2PSA and the prognosis of phi and CRPC patients calculated accordingly. This study was approved by the IRB of Gunma University Hospital (IRB 2021-092, 1983). Results: The study population of 98 patients had a median age of 73 years. The median PSA before administration of enzalutamide was 23.8 ng/ml, the median p2PSA was 208.8 pg/ml, and the median phi was 188.0. The median values of each parameter were divided into two groups, and the PSA progression free survival (PSA-PFS) and overall survival (OS) rate were compared by the Kaplan-Meier method. In the study of PSA-PFS, PSA, p2PSA, and phi could not be significant markers. In the OS study, the median OS of the PSA low group was NYR (not yet reached), the high group was 26.8 months, the p2PSA low group was NYR, the high group was 26.8 months, the phi low group was NYR, and the high group was 26.8 months. The OS was significantly better in the low- value group for each parameter (p-values 0.024, 0.034, 0.018, respectively). Conclusions: The biology of p2PSA in CRPC patients has been clarified. Although we couldn't find a clear advantage over PSA, we would like to add a study based on the data of this study.
Effect of prostate brachytherapy case volume in the community setting on oncologic outcomes.
Authors: Kevin Chang, Lufan Wang, Janet E. Cowan, Peter Carroll, Matthew R. Cooperberg
Journal: Journal of Clinical Oncology (2023)

339 Background: A volume-outcome relationship has not yet been comprehensively established for prostate cancer brachytherapy, a treatment modality that is declining in usage, with regard to cancer-specific outcomes. The goal of this study is to describe the relationship between facility brachytherapy case volume and cancer-specific outcomes in patients with localized prostate cancer. Methods: We identified patients in CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) diagnosed with localized prostate cancer between 1999-2007 and treated with brachytherapy. Only community hospital settings had sufficient documented cases for inclusion. The brachytherapy case volume of each facility was based on its total number of brachytherapy-treated prostate cancer patients with facilities above the 75th percentile categorized as high-volume facilities. The primary outcome was biochemical failure based on the Phoenix definition or receipt of salvage treatment after primary brachytherapy. We used logistic regression to compute a propensity score for on high vs low volume facility based on demographic, clinical, and treatment variables. Cumulative incidence of biochemical failure and prostate cancer specific mortality of patients were assessed with lifetable estimates, log-rank test, and Cox proportional hazards regression, adjusted for propensity score and case volume. Secondary outcomes included patient-reported UCLA Prostate Cancer scores for urinary, sexual, and bowel function and bother. Results: We identified 1,282 patients with localized prostate cancer treated with brachytherapy between 1999-2007 across 18 community facilities with median follow-up of 9 years. The median number of brachytherapy cases over the 8 study years was 210. 722 patients (56.3%) received brachytherapy at high-volume (&gt;210 cases) community facilities and 560 patients (43.7%) at low-volume (10-210 cases) facilities. High-volume facilities predominantly used Pd-103 seeds while low-volume facilities predominantly used I-125 seeds. A greater proportion of patients at low-volume facilities had pre-brachytherapy hormone therapy (47% vs 26%; p&lt;0.01). Cumulative incidence of biochemical failure at 10 years was 10.3% for high-volume facilities and 12.5% for low-volume facilities (p=0.27). Cumulative incidence of prostate cancer specific mortality at 10 years was 4.0% for high-volume facilities and 4.5% for low-volume facilities (p=0.62). Patient-reported scores of urinary, sexual, and bowel bother at 6 months following brachytherapy were comparable between the two groups. Conclusions: Patients with localized prostate cancer treated with brachytherapy at high-volume community facilities have similar rates of biochemical failure, prostate cancer specific mortality, and trends in quality of life outcomes compared to those treated at low-volume community facilities.